Phospholipase A2 hydrolyses arachidonic acid containing phospholipids, thereby providing substrate to the multiple enzymes of the arachidonic acid cascada. The metabolites of the arachidonic acid cascade are varied and include prostaglandins, thromboxanes, leukotrienes, or other hydroxylated derivatives of arachidonic acid. The role of phospholipase A2 in the formation of prostaglandins in mammalian metabolism is well known, see W. Vogt, Advances in Prostaglandins and Thromboxane Research, 3, p. 89 (1978) and P. C. Isakson, et al., Advances in Prostaglandin and Thromboxane Research, 3, page 113, (1978). Generally, these metabolites are beneficial but in certain disease processes or other conditions the excessive production of arachidonic acid metabolites causes deleterious consequences such as inflammation, erythema, platelet aggregation, or allergic responses. The inhibition of phospholipase A2 prevents these and similar conditions.
The actual inhibition of phospholipase A2 takes place on a cellular level, therefore, administration of phospholipase A2 inhibitory compounds can be by any manner that will allow for phospholipase A2 inhibition in the affected tissues or organs. The precise mechanisms of the disease processes or conditions which stimulate the arachidonic acid cascade are not clearly understood. The essential prerequisite, however, is enhanced activity of the phospholipases which provide arachidonate to the series of reactions designated as the arachidonic acid cascade. One aspect of the present invention is to block the action of the phospholipases and cut off the flow of arachidonic acid into the cascade, irrespective of the stimulus or stimuli which may be present. Thus, the inhibition of phospholipase A2 of this invention is suitable for treating seemingly unrelated diseases whose common element is the stimulation of the arachidonic acid cascade.
Hyperglycemia refers to a condition commonly found in patients suffering from mature onset diabetes mellitus or other diseases which cause impairment of pancreatic function. Hyperglycemic patients with non-insulin dependent diabetes mellitus (NIDDM) with insulin resistance exhibit elevated serum glucose levels. Failure to adequately control elevated serum glucose levels can cause myocardioischemia, stroke, peripheral vascular disease, lethargy, coma, blindness, kidney failure or death. One important means of treating these patients uses oral antidiabetic agents instead of conventional treatment for hyperglycemic conditions such as restriction of carbohydrate intake or insulin injection.